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MOLECULAR NEUROSCIENCE: Promoting Diversity

One of the most remarkable features of the mammalian nervous system is the enormous diversity (in electrophysiology, connectivity, and morphology) of neurons. The molecular codes that impart this diversity and the mechanisms by which it is generated are questions of intense interest.

Among the proteins thought to contribute to neuronal diversity are the protocadherins (Pcdh's), a family of cell surface molecules encoded by three clusters of genes, organized (much like immunoglobulin genes) into a “variable” region (which may contain 14 or more variable exons) and a “constant” region (which can have three constant exons). Pcdh transcripts containing combinations of variable and constant exons are expressed throughout the nervous system. Tasic et al. and Wang et al. show that each Pcdh variable exon is preceded by a distinct promoter and that the choice of promoter during transcription determines which variable exon is included in the pre-messenger RNA. The variable exon is then joined to a constant exon by cis splicing. In principle, if each neuron expressed several different isoforms of Pcdh, this two-step mechanism could generate millions of Pcdh-based neuronal subtypes. — PAK